Unexpected mechanochemical complexity in the mechanistic scenarios of disulfide bond reduction in alkaline solution

The reduction of disulfides has a broad importance in chemistry, biochemistry and materials science, particularly those methods that use mechanochemical activation. Here we show, using isotensional simulations, that strikingly different mechanisms govern disulfide cleavage depending on the external force. Desolvation and resolvation processes are found to be crucial, as they have a direct impact on activation free energies. The preferred pathway at moderate forces, a bimolecular SN2 attack of OH– at sulfur, competes with unimolecular C–S bond rupture at about 2 nN, and the latter even becomes barrierless at greater applied forces. Moreover, our study unveils a surprisingly rich reactivity scenario that also includes the transformation of concerted SN2 reactions into pure bond-breaking processes at specific forces. Given that these forces are easily reached in experiments, these insights will fundamentally change our understanding of mechanochemical activation in general, which is now expected to be considerably more intricate than previously thought. The controlled mechanical activation of specific covalent bonds is a rapidly expanding field in chemistry. Now, it is shown that disulfide bond reduction proceeds through different mechanisms depending on the external force applied. This strongly suggests that refined models should be used when interpreting mechanochemical experiments, particularly when sonication is involved.